Triazolo [b] pyridazines



United States Patent 3,096,329 TRIAZOLO[b]PYRIDAZINES Edgar AlfredSteck, Guilderland Township, Albany County, N.Y., assignor to SterlingDrug Inc., New York, N .Y., a corporation of Delaware No Drawing. FiledOct. 15, 1957, Ser. No. 690,195 12 Claims. (Cl. 260250) This inventionrelates to Itriazolo [b]pyridaz.ines.

The present invention resides in the concept of a composition of matterhaving a molecular structure wherein a tertiary-arninoalkylene radicalis attached through an imino bridge to the carbon atom in the 8-positionof an s-triazolo[b]pyridazine radical. This idea has been applied inactual practice and its utility demonstrated by the embodiment intangible form of several representative species of the generic conceptconstituting the claimed invention. The identifying physicalcharacteristics of several compounds embodying the invention have beenascertained and proof of molecular structure has been accomplished. Thephysical embodiments of the inventive concept herein described andclaimed are useful as sedatives, ganglionic blocking agents andanticholinesterase agents.

The tertiaryaaminoalkylenc radicals contemplated here are constituted bya well-known group of organic radicals in which: (a) two of thesubstituen-ts attached to the amino nitrogen are lower-alkyl radicals,either straight or branched chain, and these may, as is also known, bejoined to form, with the amino nitrogen, a mono-heterocycle which cancontain in the ring a second variant atom such as sulfur or oxygen; and,(b) the third substituent attached to the amino nitrogen is a loweralkylene radical which may likewise be straight or branched inconfiguration and can be substituted with any of the usual groupringssuch as hydroxy and halo. The tri-azolo[b] pyridazine radical can bearsubstituents in the 6- and 7-positions of the known types such aslower-'alkyl and monocarbocyclic aryl radicals. It will thus be apparentthat the invention is in the getting of the concept of joining, throughan im'rno bridge, of the alkylene substituent of a tertiaryaminoalkylenegroup with a triazolo[b]pyridazine in the 8-position.

The inventive concept can be embodied in physical form by thecondensation of an S-halo-s-triazolo[b]pyridazine with a tertiaryaminoalkylamine with the splitting out of hydrogen halide. The reactionis conducted at a temperalture in the range between about 100 C. andabout 250 C.

A particular aspect of the invention relates to corn-r pounds having theformula wherein R represents a lower-alkyl or a monocarbocyelic arylradical, R represents hydrogen or a lower-alkyl group, Y represents alower-alky-lene radical, hydroXysubstituted lower-alkylene radical or amonocarbocyclic aryl-substituted lower-alkylene radical in which thefree valences are on diiferent carbon atoms, and N=B represents adi-lower-alkylarnino, l-piperidyl, l-pyrrolidyl, or 4-morpho-linylradical.

In the above general Formula I, R represents a loweralkyl radical or amonocarbocyclic aryl radical. When R represents a loWer-alkyl radical itcan be straight or branched and contains (from one to about eight carbonatoms, thus including such groups as methyl, ethyl, propyl,

3,96,3-29 Patented July 2,1963

isopropyl, butyl, isobutyl, tertiary-butyl, pentyl, hexyl, isohexyl, heptyl, octyl, and the like. When R represents a monocarbocyc-lic arylgroup it is a radical of the benzene series and can be an unsubstitutedphenyl group or a phenyl group substituted by one or more substiurentsinert to the reaction conditions and reagents used in the process forpreparing the compounds. Such inert substituents include lower-.alkyl,lower-alkoxy, halogen, nitro, trifluoromethyl, and the like. A preferredclass of R, when monocarbocyclic aryl, consists of phenyl and phenylsubstituted by from one to three lower-'alkyl, lower-alkoxy or halogengroups, and two or more substituents are present they can be the same ordifferent and in any of the various positions relative to one another.The lower-alkyl and lower-alkoxy groups preferably have from one toabout four carbon atoms and thus can be methyl, ethyl, propyl,isopropyl, :butyl, isobutyl, methoxy, ethoxy, propoxy, isopropoxy,butoxy, isobutoxy, etc. The halogen substituents may be any of the fourhalogens, fluorine, chlorine, bromine or iodine. Specific examples ofthe group R, when monocar-bocyclic aryl, include phenyl, p-tolyl,p-ethylphenyl, rn-butylphenyl, o-ethoxyphenyl, rn-propoxyphenyl, pbutoxyphenyl, 3,4 dimethoxyphenyl, 2- methyl-4-rnethoxyphenyl,p-chlorophenyl, rnbrornop'henyl, 3-methoXy-4-chlorophenyl,p-fluorophenyl, and the like.

In the above general Formula I, R represents a hydrogen atom or alower-alkyl group. The lower-alkyl groups are of the same type asdefined for the group R above.

In the above general Formula I, Y represents a loweralkylene radical, ahydroXy-substituted lower-'alkylene radical or a monocarbocyclicaryl-substituted lower-alkylene radical in which the free valences areon different carbon atoms. The aliphatic portion of the lower-alkyleneor substituted lower-alkylene radicals contains from two to about sixcarbon atoms and may be straight or branched. The monocarbocyclic arylgroups, if present, are of the same type as those defined above for thegroup R. Illustrative of the groups which Y can represent are thefollowing:

In the above general Formula I, the tertiarysamino rad ical N=Brepresents a di-loweraalkylamino or a saturated heterocyclic radical. Inthe di-lower alkylarnino radicals, the term lower-alkyl includes alkylradicals containing from one to about six carbon atoms and thelower-alkyl groups can be the same or different. Thus N=B, when itrepresents a di-lower-alkylarnirro radical, includes such groups asdimethylarnino, diethylarnino, ethylmethylamino, dipropylamino,diisopropylarnino, dibutylamino, dipentylamino, dihexylarnino, and thelike. N=B, when it represents a saturated heterocyclic group, includessuch 1 groups as l-piperidyl, l-pyrrolidyl, 4morpholinyl andl-ower-alkylated derivatives thereof, for example, 2-methyl-l-piperidyl,3-ethyl-4-morpho1inyl, 2,5-dimethyl-1-pyrrolidyl, and the like.

The compounds of Formula I are prepared by the fol lowing series ofreactions:

When a fi-keto ester (II) is heated with l-amino-1,-2, 4-triazole (III)there is obtained an '8-hydroxy-s-triazolo- [bJpyridazine ("IV). The 8hydroxy compound IV is then reacted with a phosphorus oxyhalide, POXwhere X is a halogen, preferably chlorine or bromine, to give the8-halo-s-triazolo[b]pyridazine (V). The compound of Formula V wherein Xis iodine can be obtained by reacting the hydroxy compound IV withphosphorus and iodine. The compound V then is reacted with atertiary-aminoalkylamino, H NYN=B, to give the compound of Formula I.The condensation of V and H N-YN=B is carried out by heating thereactants together at a temperature between about 100 C. and about 250C., optionally in the presence of various substances which serve ascatalysts, for example phenols and alkali iodides. Since hydrogen halideis split out during the reaction there is produced in the reactionmixture some hydrohalide salt of the product I and/or of any excess HN--YN=B. In working up the reaction mixture it is preferred toneutralize all hydrohalide salts with an excess of a strong base and toremove the volatile materials, including excess H NY-N=B by steamdistillation.

The structure of the compounds of the invention is established by thetypes of reactions employed in their preparation, by chemical analysis,and by the fact that the intermediates of Formula IV are a known classof compounds.

Acid-addition salts of the compounds of the above general Formula I areprepared either by dissolving the free base in an aqueous solutioncontaining the appropriate acid and isolating the salt formed byevaporating the solution, or by reacting the free base and acid in anorganic solvent, in which case the salt separates directly or can beobtained by concentration of the solution. Preferred types ofacid-addition salts are those derived from mineral acids such ashydrochloric acid, hydrobrornic acid, hydroiodic acid, nitric acid,sulfuric acid and phosphoric acid; and organic acids such as aceticacid, oxalic acid, citric acid, lactic acid, quinic acid, tartaric acid,and the like.

The quaternary ammonium salts of the above general Formula I areprepared by mixing the free base and the quaternizing agent, preferablyin an organic solvent. Heating may be used to facilitate the reaction,although salt formation usually takes place readily at room temperature.The quaternary ammonium salt separates directly or can be obtained byconcentration of the solution. Preferred types of quaternizing agentsinclude alkyl, alkenyl or aralkyl esters of inorganic acids or organicsulfonic acids, thus including such compounds as methyl chloride, methylbromide, methyl iodide, ethyl bromide, propyl chloride, allyl chloride,allyl bromide, methyl sulfate, methyl benzenesulfonate, methylp-toluenesulfonate, benzyl chloride, benzyl bromide, and substitutedbenzyl halides, such as p-chlorobenzyl chloride, p-nitrobenzyl chloride,o-chlorobenzyl chloride, p-methoxybenzyl chloride, and the like.

One quaternary ammonium salt can be converted to another in which theanion is difierent. If the anion of the quaternary salt forms awater-insoluble silver salt, which is usually the case, the quaternarysalt can be reacted with silver oxide in aqueous medium to form asolution of the corresponding quaternary ammonium hydroxide. The lattercan then be neutralized with any desired acid, weak or strong, toproduce a new quaternary ammonium salt in which the anion is differentfrom that of the original quaternary salt. In this way quaternaryammonium salts in which the anion is derived from a weak acid can beobtained.

Pharmacological evaluation of the compounds of the invention hasdemonstrated that the acid-addition salt forms of the compounds possessuseful sedative effects in that they potentiate the sleeping timeinduced by administration of barbiturates. The quaternary ammonium saltforms of the compounds have been demonstrated to be useful as ganglionicblocking agents and anticholinesterase agents.

Preferred types of acid-addition and quaternary am monium salts arethose which are pharmacologically acceptable; that is, those whoseanions are relatively innocuous to animal organisms in pharmacologicaldoses of the salts. However, all salts, whether pharmacologicallyacceptable or not, are useful as intermediates in the preparation andpurification of the free bases and as crystalline, characterizingderivatives.

The compounds of the invention can be prepared for use by dissolving asalt form of the compounds in water (or an equivalent amount of anon-toxic acid if the free base is used) under sterile conditions, or ina physiologically compatible aqueous medium such as saline, and storedin ampules for parenteral administration. Alternatively, they can beincorporated with excipients in tablet or capsule form for oraladministration.

The following examples will further illustrate the invention without thelatter being limited thereto.

EXAMPLE 1 (a) 6 methyl 8 -hydroxy s triazol0[b]pyridazine. A mixture of245 g. of 4-amino-l,2,4-triazole and 500 cc. of ethyl acetoacetate wasrefluxed at 125140 C. for nine hours, removing the ethyl alcohol formedby distillation at intervals of from one and one-half to two andone-half hours. During this time an additional 250 cc. of ethylacetoacetate was added in portions. The reaction mixture was cooled toC., 250 cc. of Water was added and the solid material was collected byfiltration. The latter was triturated with water, alcohol and ether,giving 316 g. of 6-methyl-8-hydroxy-s-triazolo[b]pyridazine, which wassufficiently pure to use in the succeeding reactions. The compound wasfurther purified by recrystallization from acetic acid, giving colorlessmicrocrystals, MP. 304306 C. (dec.) (corn).

Analysis-Calm. for C H N O: C, 48.32; H, 3.38; N, 37.57. Found: C,48.22; H, 3.90; N, 37.27.

(b) 6-methyl-8-chl0ro-s-triazol0 [b] pyridazine.-A mixture of 316 g. of6-methyl-8-hydroxy-s-triazolo[b]pyridazine and 3 liters of phosphorusoxychloride was refluxed for five and one-half hours. Most of the excessphosphorus oxychloride was then removed at reduced pressure (Waterpump), and the residue was poured into ice and made basic with ammoniumhydroxide. The solid material was collected by filtration andrecrystallized twice from water (about 4 liters) using activatedcharcoal for decolorizing purposes. There was thus obtained 227 g. of6-methyl8-chloro-s-triazolo[b]pyridazine in the form of colorlessneedles, M.P. 190190.5 C. (uncorr.). Further product was obtained byextraction of the combined aqueous mother liquors with methylenedichloride, and concentration of the extracts.

Analysis.-Calcd. for C H ClN C, 42.74; H, 2.99; Cl, 21.03. Found: C,42.43; H, 3.32; Cl, 21.20.

Replacement of the phosphorus oxychloride in the preceding preparationby a molar equivalent amount of phosphorus oxybromide or of phosphorusand iodine, yields, respectively,6-methyl-S-bromo-s-triazol-o[b]pyridazine or6-methy1-8-iodos-triazolo[b]pyridazine.

(c) 6 methyl 8 (3 dierhylaminopropylamina) -s-triaz0la[b]pyridazine.-Amixture of 16.8 g. of 6-methyl-8- chloro-s-triazolo[b]pyridazine and 25g. of phenol was heated to l10 C. There was then added 26 g. of 3-diethylarninopropylamine in four portions over a period of aboutone-half hour. A trace of potassium iodide was added and the reactionmixture was heated at -170 C for seventeen hours. After cooling, thereaction mixture was poured into ice and excess sodium hydroxide andextracted with methylene dichloride. The methylene dichloride extractswere concentrated to a small volume and steam distilled until 400 cc. ofdistillate was collected. The undistilled residue was extracted withmethylene dichloride, and the extracts were dried over anhydrous sodiumsulfate and concentrated to dryness. The residue (26.:1 g.) wasdissolved in 500 cc. of boiling petroleum ether (Skellysol-ve B), andthe supernatant solution was decanted from an insoluble dark tar andcooled in an icesalt bath. There separated 18.3 g. of =6-methyl-8-(3-diethylaminopropylamino -s-triazolo [b] pyridazine, M.P. 9296 C. Arecrystallization from petroleum ether gave a cream-colored solid withthe M.P. 94.5-97 C. (corr.).

Analysis.-Calcd. for C H N C, 59.51; H, 8.45; N, 32.04. Found: C, 59.54;H, 8.36; N, 32.31.

A 0.5% solution of 6-methyl-8-(3-diethy1aminopropyl-'arnino)-s-triazolo[blpyridazine in dilute acetic acid administeredsubcutaneously to mice at a dose level of 50 mg./kg. of body Weightforty-five minutes before an interperitoneal dose of hexobarbital sodiumcaused a 69% increase in sleeping time. The acute toxicity (approximatelethal dose, ALD of 6-methyl8-(3-diethylaminopropylamino) -s-triazolo[b] pyridazine, administered interperitoneal ly to mice, was 210 mg./kg.

in the procedure just described the6-methyl-8-chloros-triazolo[b]pyridazine can be replaced by molarequivalent amounts of either 6-met-hy1-8-bromo-s-triazolo[b]pyridazineor 6-methyl-8-iodo-s-triazolo [b]pyridazine.

Replacement of the 3-diethylarninopropylarnino in the procedure justdescribed by molar equivalent amounts of 2-( l-pyrrolidyl ethylamine,2-( l-piperidyD-ethylamine, 2- (4-morpholiny1)ethylarnine, or2-(2-methyl-l-pyrro1idyl)- ethylamine, yields, respectively,6-methyl-8-[2-(1-pyrrolidyl ethylamino] -s-t-riazolo [b] pyridazine,6-rnethyl-8- [2-( l-piperidyl) ethylamino] -s triazolo [b]pyridazine, 6-

methyl =8 [2 (4 morpholinyl)ethylamino] s triazolo[b]pyridazine, or6-methyl-8-[2-(2-methyl-1-pyrrolidyl ethylamino] -s-tr-iazolo [b]pyridazine.

A portion of the6-methyl-'8-(3-diethylaminopropylamino)-s-triazolo[b]pyridazine wasconverted to its oxalate salt by treating an ethyl acetate solution ofthe free base with an excess of oxalic acid. The salt which separatedwas recrystallized from aqueous ethanol by first dissolving in water andthen adding ethanol. The oxalate was obtained in the form of colorlessblades, M.P. Z10.5212.5 C. (dec.) (corr.).

AnaZysis.-Calcd. for C H N C H O C, 51.12; H, 6.86; N, 23.85. Found: C,51.40; H, 6.88; N, 24.10.

'6 methyl 8 (3 diethylaminopropylarnirro) s triazolo[b]pyridazine wasconverted to its methiodide salt by warming a methanol solution of thefree base with an excess of methyl iodide. The methiodide salt wascaused to precipitate by addition of ether. After two recrystallizationsfrom a methanol-ether mixture, the methiodide salt was obtained in theform of colorless needles, M.P. 204.5207 C. i(corr.).

Analysis.-Calcd. tor C H IN N, 20.79; I, 31.39. Found: N, 20.99; I,31.28.

The methiodide salt of6-me-thyl-8-(3-diethylaminopropylamino)-s-triazolo [b] pyridazine whentested by the bilateral carotid occlusion method in barbitalized dogsshowed a ganglionic blocking activity against both parasympathetic andsympathetic ganglia equal to that of tetraethylarnrnonium bromide. Thequaternary ammonium salt also showed an anticholinesterase activity 6%that of neostigm-ine methylsulfate as measured by the electrometricmethod for the determination of red blood cell and plasma cholinesteraseactivity [Miche1, J. Lab. Clin. Med. 34, 1564 (1949)].

l no)-s-triazol0[b]pyridazine was prepared in 71% yield by reacting6-rnethyl-8-chloro-s-triazol0[b]pyridazine and4-diethylamino-l-methylbutylamine according to the manipulativeprocedure described above in Example '1, part (c). The free base Wasobtained in the form of a yellow oil, -B.P. about 200 C. (0.06 mm).

Analysis.Calcd. for C H N N (basic), 9.65. Found: N (basic), 9.60.

The oxalate salt of6-methyl-8-(4-diethylamino-lmethylbutylamino)-s-triazolo[bJpyridazinewas obtained from the free base in 74.5% yield in the form of colorlessspherules, M.P. 2l7.52118.5 C. (coma), when recrystallized from ethanol.

Analysis.-C-alcd. for C H N .C H O C, 53.66; H, 7.42; N, 22.09. Found:C, 53.75; H, 7.21; N, 21.92.

EXAMPLE 3 6 methyl 8 (3 diethylamino 2hydroxypropylamino)-s-Iriaz0lo[b]pyridazine was obtained in 81% yield byreacting 6-methyl-8-ohloro-s-triazolo[b] pyridazine and3-diethylamino-2-hydroxypropylamine according to the manipulativeprocedure described above in Example 1, part (c). The free base wasobtained in the form of colorless platelets, M.P. 126-127 C., whenrecrystallized from heptane.

Analysis.Calcd. 'for C H N O: C, 56.09; H, 7.97; N, 30.19. Found: C,55.90; H, 7.67; N, 30.20.

The oxalate salt of6-methyl-8-(3-diethylamino-2-hydroxypropylamino)-s-triazolo[b]pyridazinewas obtained from the free base in 68% yield in the form of colorlessmicrocrystals, M.P. 41675470 C. (dec.) (cor-n), when recrystallized fromethanol.

Analysis.Calcd. for C H N O.C H O C, 48.90; H, 6.57; N, 22.82. Found: C,49.113; H, 6.75; N, 23.21.

EXAMPLE 4 6-m ethyl-8-(2 diethylamin'oethylam ino)-s-triaz0l0[b]pyridazz'ne was prepared in 88% yield by reacting 6-rnethyl-8-ch-loro-s-triazolo[b]pyridazine and 2 diethy laminoethylamineaccording to the manipulative procedure described above in Example 1,part (c). The free base was obtained in the form of colorless leaflets,M.P. 151.5- 152.5 C., when recrystallized from heptane.

Analysis-Called. for C H N C, 58.04; H, 8.12; N, 33.85. Found: C, 58.15;H, 7.94; N, 34.15.

The oxalate salt of6-methyl-8-(2-diethylaminoethylamino)-s-triazolo[b]pyridazine wasobtained from the free base in 71% yield in the form of colorlessmicrocrystals, M.P. 173-174 C. (dec.) (corn), when recrystallized fromethanol.

Analysis.-Calcd. for C H N .C H O C, 49.69; H, 6.56; N, 24.84. Found: C,49.73; H, 6.57; N, 25.08.

EXAMPLE 5 6-methyl-8-(4 diethyldm inobutylamino)-s-triaz0l0[b]pyridazz'ne was prepared in 77% yield by reacting 6-rnethyl-8-chloro-s-triazolo[b]pyridazine and 4-diethylaminobutylami-neaccording to the manipulative procedure described above in Example 1,part (c). The free base was obtained in the form of colorlessmicrocrystals, M.P. 8181.5 C., when recrystallized from hexane.

An alysis.Calcd. for C H N C, 60.84; H, 8.75; N, 30.41. Found: C, 60.52;H, 9.01; N, 30.19.

The oxalate salt of 6-methyl-8-(4-diethylaminobutylaimino)-s-triazo1o[b]pyridazine was obtainedfrom the free base in 64% yield in the form of colorless flakes, M.P.144.5146.5 C. (corn), when recrystallized from aqueous ethanol.

EXAMPLE 6 6-methyl-8-(4 dibutylalm inobutylamino)-s-triazol0[b]pyridazine Was prepared in 59% yield by reacting 6-methyl-8-chloro-s-triazolo[blpyridazine and 4-dibutylaminobutylamineaccording to the manipulative procedure described above in Example 1,part (c). The free base was obtained in the form of colorless platelets,M.P. 76- 77 0., when recrystallized from hexane.

An.a lysis.--Calcd. for C H N C, 65.02; H, 9.70; N, 25.28. Found: C,64.98; H, 9.82; N, 25.12.

The oxalate salt of6-met-hyl-8-(4-dibutylarninobutylamino)-s-tri-azolo[b]pyridazine wasobtained from the free base in 67% yield in the form of colorlessmicroorystals, M.P. 158160 C. (corn) when recrystallized from aqueousethanol.

EXAMPLE 7 6-methyl-8-[2-(4chlorophenyl)-4-diethylamin0butylamino]-s-triazolo[b]pyridazine wasprepared from 8.4 g. of 6-methyl-8-chloro-s-triazolo[b]pyridazine and25.5 lg. of 2-(4-chlorophenyl)-4-diethylarninobutylamine in 15 cc. ofphenol according to the manipulative procedure described above inExample 1, part (c). The crude free base after one crystallization frompetroleum ether (Skellyso-lve C), was converted to the oxalate salt inethyl acetate solution. The resulting crystalline material wasrecrystallized from alcohol containing a small amount of water, giving9.9 g. (67%) of 6-rnethyl-8-[2-(4-chlorophenyl)-4diethylaminobutylamino[-s-triazolo[-bJpyridazine oxalate in the form offine colorless needles, M.P. 199.5-201" C. (corn).

Analysis.calcd. for c20H27C1N .C2 ?I204: C, H, 6.12; N (basic), 5.87.Found: C, 55.62; H, 7.62; N (basic), 5.80. Ca-lcd: Base, 81.12; acid,18.88. Found: Base, 80.93; acid, 18.90.

A portion of the oxalate salt was converted to the free base byneutralization in aqueous medium and recrystallization of the productfrom petroleum ether (Skellysolve C), giving6-methyl-8-[2-(4-chlorophenyl)4-diethylaminobutylamino]-s-triazolo[b]pyridazine in the form ofyellowish micro-crystals, MP. 137-138 C. (corn).

Analysis.Calcd. for C H CIN C, 62.08; H, 7.04; N, 21.72. Found: C,61.90; H, 7.60; N, 21.78.

EXAMPLE 8 (a) 6,7-dimethyI-S-hydroxy-s-rriazolo[b]pyridazine wasprepared from 4-amino-1,2,4-triazole and ethyl tit-methylacetoacet-ateaccording to the manipulative procedure de scribed above in Example 1,part (a). There was thus obtained a 75% yield of6,7-dimethyl-S-hydroxy-s-triazolo [b]pyridazine in the form of colorlessneedles, M.P. 2635-2665 C. (corn), when recrystallized from aqueousethanol.

Analysis.-Oa-lcd. for C H N O: C, 51.21; H, 4.91; N, 34.13. Found: C,51.20; H, 5.09; N, 34.29.

([1) 6,7 -dzmethy l-8-ch loro-s-triazolo b] pyridazine was prepared byreacting 6,7-dirnethyl-8-hydroxy-s-triazolo [bJpyridazine and phosphorusoxychloride according to the manipulative procedure described above inExample 1, part (b). There was thus obtained an 86% yield of6,7-dimethyl-8-chloro-s-triazolo[b]pyridazine as pale yellow needles,M.P. 147-149 C., when recrystallized from 90% ethanol. This product wassublimed at 130 C. at 6 10 mm., and then recrystallized from ethanol;M.P. 153.5154 C.

Analysis.--Calcd. for CqHqO1N C, 46.03; H, 3.86; N, 30.68. Found: C,45.87; H, 4.21; N, 30.82.

(c) 6,7-dimerhyl-8-(2 diethylam inoethylamino)-s-triazol[b]pyridazinewas prepared in 67.5% yield by reacting6,7-dimethyl-8-chloro-s-triazolo[b]pyridazine andZ-diethylaminoethylarnine according to the manipulative proceduredescribed above in Example 1, part (c). The free base was obtained inthe form of cream-colored blades, M.P. 96.598 C., when recrystallizedfrom cyclohexane.

An alysis-Calcd. for C H N C, 59.51; H, 8.45; N (basic), 10.68. Found:C, 59.57; H, 8.71; N (basic), 10.60.

The oxalate salt of6,7-dimethyl-8-(Z-diethylaminoethylamino)-s-triazolo[b]pyridazine wasobtained from the free base in 79% yield in the form of colorlessneedles, M.P. 212-215 C. (corn), when recrystallized from aqueousethanol.

6 EXAMPLE 9 6,7-dim'ethyl-8-(4 diethylamino-I-methylbutylam ino)-s-triazol0[b] pyrida'zine was prepared in 50.5% yield by reacting6,7-dimethyl-8-chloro-s-triazolo[b]pyridazine and4-diethylamino-l-methylbutylamine according to the manipulativeprocedure described above in Example 1, part (c). The free base wasobtained in the form of colorless blades, M.P. 9798.5 0, whenrecrystallized from cyclohexane.

Analysis.Ca1cd. for C H N C, 63.12; H, 9.27; N (basic), 9.20. Found: C,63.60; H, 9.35; N (basic), 9.51.

The 'methiodide salt of6,7-dirnethyl-8-(4-diethylaminol-methylbutylamino) striazolo[b]pyridazine was obtained from the free base in 63% yield inthe form of colorless rhoinbs, M.P. 195.5199.5 C. (corn), whenrecrystallized from a methanol-ether mixture.

Analysis.--Calcd. for C H IN I, 28.43; N, 18.83. Found: 1, 28.30; N,18.76.

EXAMPLE 10 (a) 6-methyl-7-heplyl-8-hydr0xy s triaz0l0[b]pyridazine wasprepared in 33% yield by reacting 4-amino- 1,2,4-triazole and ethyltt-heptylacetoacetate according to the manipulative procedure describedabove in Example 1, part (a). The6-rnethyl-7-heptyl-B-hydroxy-s-triazolo [b]pyridazine was obtained inthe form of colorless blades, M.P. 17 0171 C. (corn), when crystallizedfrom ethanol.

Analysis.Calcd. for C H N O: C, 62.88; H, 8.12; N, 22.56. Found: C,63.01; H, 8.31; N, 22.62.

(b) 6-methyl-7-lzepzyl-8-chl0r0 s triaz0l0[b]pyridazine can be preparedby reacting 6-methyl-7-heptyl-8- hydroxy-s-triazolo[bJpyridazine andphosphorus oxychloride according to the manipulative procedure describedabove in Example 1, part (b).

(c) 6-methyl-7-heptyl-8-(2-dimethylaminoethylamina)-s-triazolo[b]pyridazine can be obtained by reacting 6-rnethyl-7-heptyl8-chloro-s-triazolo[ b]pyridazine and2-dimethylaminoethylamine according to the manipulative proceduredescribed above in Example 1, part (0).

EXAMPLE 11 (a) 6-(4-chl0r0p'henyl) -8-hydr0xy-s-triaz0l0[b] pyridazine-Amixture of 253 g. of ethyl p-chlorobenzoylacetate and 84 g. of4-amino-1,2,4-triazole was refluxed at -150 C. for four hours, duringwhich period 40 cc. of ethanol Was collected by distillation. Aftercooling somewhat, water was added to the reaction mixture and the solidmaterial was collected by filtration. The latter was triturated withwater and with cold ethanol and recrystallized from 5 liters of aceticacid, using activated charcoal for decolorizing purposes, giving 63 g.of 6-(4- chlorophenyl)-8-hydroxy s triazolo[b] pyridazine, M.P. above320 C.

Analysis.-Calcd. 'for C I-l ClN O: C, 53.56; H, 2.86; Cl, 14.37; N,22.72. Found: C, 53.81; H, 2.68; Cl, 14.66; N, 22.67.

(b) 6-(4-chl0rophenyl)-8-chl0r0 s triazolo[b]pyridazine was prepared in77% yield by reacting 6-(4-chlorophenyl)-8-hydroxy-s-triazolo[blpyridazine and phosphorus oxychlorideaccording to the manipulative procedure described above in Example 1,part (b). The 6-(4-chloro-phenyl)-8-chloro-s-triazolo[blpyridazine wasobtained in the form of brick-red needles, M.P. 240.524l.5 C. (corn),when recrystallized from aqueous dioxane.

Analysis.Calcd. for C11H15C12N4I C, H, N, 21.14. Found: C, 49.63; H,2.27; N, 20.99.

(c) 6-(4-chl0r0phenyl)- 8-(3-diethylanzino-Z-hydroxypropylamino)-s-triaz0l0[b]pyridazine wasprepared in 41% yield by reacting 6-(4-chlorophenyl)-8-chloro-s-triazolo[-b]pyridazine and 3-diethylamino-Z-hydroxypropylamine according tothe manipulative procedure described above in Example 1, part (c). Thefree base Was obtained in the form of colorless prismatic needles, M.P.

191.5-192.5 C. (corn), when recrystallized from butanol.

Analysis.-Calcd. for C H ClN O: C, 57.67; H, 6.18; N, 22.43. Found: C,57.65; H, 5.89; N, 22.60.

By replacement of the ethyl p-chlorobenzoylacetate in part (a) ofExample 11 by a molar equivalent amount of ethyl benzoylacetate, ethylp-toluylacetate, ethyl mmethoxybenzoylacetate, ethyl3,4-dimethoxybenzylacetate, ethyl 3-bromo-4-methoxybenzoylacetate, orethyl 3,4,5- trimethoxybenzoylacetate, and carrying out the manipulativeprocedures described in parts (a), (b) and (c) of Example 11, there canbe obtained, respectively, 6-phenyl- 8-(3 diethylamino 2hydroxypropylamino)-s-triazol [=b] pyridazine, 6- (4-methylphenyl -8-3-diethylamino-2- hydroxypropylamine)-s-triazolo [-b] pyridazine,6-(3-methoxyphenyl) -8- 3 -diethylamino-21hydroxypropylamino) s-triazolo[b]pyridazine,6-(3,4-dimethoxyphenyl)-8-(3-diethylamino-2-hydroxypropylamino) striazolo[b]pyridazine, 6- 3-bromo-4-1nethoxyphenyl -8- 3-diethylamino-2-hydroxypropylamino)-s-triazo1o[b]pyridazine, or 6-(3, 4,5trimethoxyphenyl)-8-(3-diethylamino-2-hydroxypropylamino) -s-triazolo[b] pyridazine.

EXAMPLE 12 6 (4 chlorophenyl) 8 (4diethylamino-I-methylbutylamino)-s-triaz0l0[b] pyridazine was preparedin 39% yield by reacting 6-(4-chlorophenyl)-8-chloro-s-triazolo-[b]pyridazine and 4-diethylamino-lamethylbutylamine according to themanipulative procedure described above in Example 1, part (c). The freebase was obtained in the form of colorless microcrystals, M.P.125.5-126.5 C. (corr.), when recrystallized from ether.

Analysis.Calcd. for CgoHgqClNeI C, 62.08; H, 7.04; N, 21.72. Found: C,61.89; H, 6.99; N, 21.70.

This application is a continuation-in-part of my copending application,Serial No. 592,751, filed June 211, 1956, now abandoned.

I claim: 11. A compound having the formula NHYN=B R N N wherein R is amember of the group consisting of loweralkyl and monocarbocyclic aryl, Ris a member of the group consisting of hydrogen and lower-alkyl, Y is amember of the group consisting of lowepalky-lene, hyd-roxylower-alkylene and monocarbocyclic aryl loweralkylene, in which the freevalences are on difierent carbon atoms, and N=B is a member of the groupconsisting of di-loWer-alkylamino, l-pyrrolidyl, l-piperidyl, and4-morpholinyl; said monocarbocyclic aryl in each instance being a memberof the group consisting of phenyl and phenyl substituted by from one tothree groups selected from lower-alkyl, lower-alkoxy and halogen.

2. A compound having the formula wherein R is lower-alkyl, R ishydrogen, Y is loweralkylene in which the free valences are on difierentcarbon atoms, and N=B is di-lower-allkyiamino.

3. A compound having the formula l N N 10 wherein R is lower-'alkyl, Ris lower-alkyl, Y is loweralkylene in which the tree valences are ondifferent carbon atoms, and N=B is di-lower-alkylamino.

4. A compound having the formula wherein R is lower-alky-l, R ishydrogen, Y is hydroxylowerailkylene in which the free valences are ondifferent carbon atoms, and N=B is di-lo wer-alkylamino.

5. A compound having the formula wherein R is phenyl, R is hydrogen, Yis hydroxy-loweralkylene in which the free valences are on diiferentcarbon atoms, and N=B is di-lowepalkylamino.

6. A compound having the formula where-in R is lower-alkyl, R ishydrogen, Y is phenyllowver-alkylene in which the free valences are ondifferent carbon atoms, and -N=B is di-lower-alkylamino.

7. 6 methyl 8 (3 diethylaminopropylamino) striazolo [b] pyridazine.

8. 6,7 dimethyl 8 (2 diethylaminoethylamino)- s-triazolo[b]pyridazine.

9. 6 methyl 8 (3 diethylamino 2 hydroxypro pylamino -s-triazolo [b]pyridazine.

10. 6 (4 ch-lorophenyl) 8 (3 diethylamino 2- hydroxypropylamino) -s-triazolo [b] pyridazine.

11. 6 methyl 8 [2 (4 chlorophenyl) 4 diethylaminobutylami no]-s-triazolo [b pyridazine.

12. A compound selected from the group consisting of 02115IfHCHflCHzOHfl-N CgHs 1 CH3 and CgHg; NHGHaCHz-N CH N N References Citedin the file of this patent UNITED STATES PATENTS 2,483,434 RieveschlOct. 4, 1949 2,700,040 Ullyot Ian. 18, 1955 2,940,974 Surrey June 14,1960 OTHER REFERENCES Takahayshi, J. Pharm. Soc., Japan, vol. 26 (1956),pages 7657.

Burger (Editor), Medicinal Chemistry (second edition, 1960), pages592-600.

1. A COMPOUND HAVING THE FORMULA